To explore the effect of Shexiang baoxin pills on clopidogrel resistance in patients with acute coronary syndrome (ACS). 131 cases with ACS combining with clopidogrel resistance admitted to our hospital during March 2013 to November 2015 were recruited in this study and were divided into observation group (66 cases) and control group (65 cases) according to the random number table method. And the patients in observation group were given clopidogrel with Shexiang baoxin pills therapy while the control group clopidogrel therapy to observe the platelet aggregation rate, heart rate variability (HRV), and serum level of matrix metalloproteinase-2 (MMP-2). After treatment, the platelet aggregation rate in observation group was significantly less than the group before treatment and that of control group (P<0.05); And before treatment, the serum level of MMP-2 and HRV of the two groups were not statistically significant (P>0.05). But after treatment, the serum level of MMP-2 and HRV of the observation group were significantly lower and better respectively than the observation group before treatment and control group (P<0.05). Shexiang baoxin pill plays an active role in reducing clopidogrel resistance in patients with ACS, lowering platelet aggregation rate and serum level of MMP-2, improving HRV in the body.